Activation of microglia and neuronal excitotoxicity are postulated to underlie the neurodegeneration that frequently accompanies systemic ADS. Cannabinoids, drugs given to AIDS patients clinically and widely used illicitly, modulate excitatory neurotransmission and excitotoxicity. This proposal addresses the overall question of how HIV-1 proteins, chemokines, and cannabinoids influence microglial function and glutamatergic synaptic transmission to ultimately affect neuronal survival. Four specific aims are proposed. 1) HIV-1 proteins and chemokines activate a novel chemokine receptor signaling cascade in microglia. The hypothesis that downstream elements of this cascade provide branch points to modulate specific cellular functions will be tested. The kinases and channels in this cascade may be useful pharmacologic targets for altering the course of HIV-1 associated dementia. 2) Excitotoxic Ca2+ increases degrade the plasma membrane Ca2+ pump in neurons. The hypothesis that loss of Ca2+ pump activity contributes to excitotoxic neurodegeneration and that enhanced Ca2+ efflux is neuroprotective will be tested. The plasma membrane Ca2+ pump may be an important point of cross talk between the necrotic and apoptotic cell death pathways. 3) Cognitive impairment precedes overt neuronal loss in HIV-1 associated dementia. The hypothesis that neurotoxins released by microglia induce a loss of functional synapses will be tested. Synaptic function may be sensitive to lower concentrations of neurotoxins than cell survival. 4) Cannabinoids protect from excitotoxicity, inhibit the formation of new functional synapses and their effects on synaptic transmission desensitize. The hypothesis that withdrawal of cannabinoids from tolerant cultures will reveal compensatory changes in synaptic transmission and endocannabinoid signaling that increase neuronal sensitivity to excitotoxic stimuli will be tested. These studies will clarify the role of endocannabinoids in CNS stress responses and the effects of exogenous cannabinoids on synaptic plasticity. In addition to providing a better understanding of HIV-1 neurotoxicity and its modulation by cannabinoids, these studies will contribute more generally to understanding chemokine function in microglia, the role of Ca2+ clearance in neurotoxicity and the modulation of synaptic function by G-protein-coupled receptors and neurotoxins.